Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
2~)0599Z
2S oc~obe~ 1989
P-2~9~
~cJi~lnD~.
Thi~ lnv~ntion r~lat~s to granulat~ ~or ~ulti-
particul~te controll~d-r~lea-o oral compo~itlon6 oo~prl~ing
biologic~l~y ~ctlvo ubotanc~-, targetod to pr-aetermincd
part~ ~t the int-~tlne and o~p-cially to tho lower part
t~r~o~, and to oral oompo-Ltion~, oontainlng ~uch granu-
l~tec
Wh~n th~ actlve prlnclplo of an oral aompo~ition ~in a
1~ ingl--un$t or multip~rtlaulato product) 1~ to b~ targeted to
the ~nto~tin-, it l- oonv-ntlon~lly co~ted by a 6ingl~ or
multipl- layor of an aald-r~ tant and~or ~lowly-r~ cing
coatlng Curr-~tly ~ oono$~-ra~1- numb-r o~ ~ubst~nc-- ~nd
~lxtur-~ Are known ~or u~ in uch coatings European Pa~nt
Appllaation 0040~0 d--cri~ th- aoatlng o~ a core contain-
ing ~ th-r~poutlc~lly actL~ ~b-t~na- ~y a ~ingl- layer com-
prl~ing an ~aid-r~latant polymor and a wat-r-in~oluble poly-
m r. A multlpl--layer-d co~tlng i~ d~-cri~d ln U ~ Pat~nt
S,431,338~ wh- r - ~ d~u~-aontainLng nucleu- i~ aoat~d ~ucce-a-
~v~ly wlth ~n acl~ colubl~, alk-li-r~ tant mat~rlnl, a
w~tQr-~olubl~ lnterm-dl-to lay-r ~nd ~n nutar lk~ oluble,
acid-re~i~tant layer In practioo, the coat-d p~ep~ation-
are o~ten unrellablo and b~ o~ their production l~ cumber-
~ome ~her-~or-, A n~ed ~Xi~tB rOr lmprovem-n~ o~ int~tinal
30 ~rug t~r~ting
A rurther dev-lopm~nt i~ t~ use th~ con~pt o~ ~olld
dl~p-rBion or th- ACtiVe principle ln the xole~--modlryinq
~ub~tance a- an al~ernatlv~ to coating the activ~ principle
3S with th~ relea~e-modlrylng sub~nco A ~olid di~p~r~on,
whlch i~ to b- cloarly dl~tlnguished ~rom Bimplo m~chanlo~l
mixe~, h~- b-en d~in-d a~ a di~per~lon Or one or mot~ ~otive
ingredi-nts in an inor~ ex~lpi-nt at solid ~a~e prepared by
the meltlng ~ruaion)~ ~olvcnt, or melting-~olvent m~hod
;~005~39~
-- 2 --
(J.L. ~ord, Phanl~ Aata ~lv. ~'7, ~,, ~9). Tho conoopt of
solld dlopcrJion was lntro~u~d by X. Sokiguch and N. Obl
(C:ha~. 2h~r~. Bull. ~, ~, 86C~, to l~lnpro-re the bio-
Dva~ lAbility oY a poorly wat~r-~olu~le drug ~y dis-p~rslng it
5 ln a w~er-~olubl~ excl~ient. ~rh~ bulk of seub~quent publica-
t~ orlo to dat~ con~.~rnoe ~uah ~nh~no~d-rel~a~e p~oduct~.
But it h~ aloo bson re~ognized tha~ aL ~imilar ~oncel?t can b~
appllod to Isu~t~ined-r~l~a-l~ produ~t~. On~ ~xample i~
Japano~ Pat~nt Appl$catlon ~Xolca~) 61,07~,733, ~hlc:h dis-
19 clos~ an a~norphou~ solid preparation lntend~d to dissolva intho lnt~tine, oompri~ing ~a) ~ non-~erold typ~ antl-
$nfl-mmate~ry agent ouch ~o ~ ndo~th~ain and (b) on~ or r~ore
pH-depond~nt high molocular ¢ompound~, ~uc~h as a aopolymer o~
~oth~ nlic ~cid a~ methyl ~-thacryl~to. It i~ ~anu~a~tursd
~y di4~01ving (~) and ~b) ln a ~ommon ~olY~nt, r~ovln~ ~h~
6~1~e~t ~nd pulvori~inq ~h~ ~olid ~orm~d. Only graln~ falllng
wi~in th~ reg~ired ~i2e ar~ u~e~, whlah o~ cou~oo l~volves
01~8 Or subutanao. B~3~ide~ wh~n thaf;o ~rainc ar~ to be
further prooes~ into tablot~, tboy hAvo to b~ gran~la~ed
~irst, ~ proçe~s ln the cours~ o~ whioh tho~e oxlst~ a danger
of adver~ly in~luenclng tho glass-llke consl~t~ncy o~ the
~oll~ dioporsion, ~hu~ de~eatln~ lt~ purposo o~ acid
re~tance.
Tho deposltion o~ solld dl~p~r~ion~ ~ th~ ~nhanccd-
roloa~- typ- on wat~r-~olubl~ carrier par~lcles ~uch a~
~actose, or on partiole~ Or calciu~ hydrogen phosphate which
18 solu~le ln gastrlc rlul~ ha~ be~n proposea by K.H. Klm and
C.J. Jarow~ki ~J. Pharm. ~ci. ~ 211, 1~) and by
J.~. Ford And M.H. Ru~in~tein ~Pharm. Act~ ~elv. ~3
r6l~pcatlvely.
Th~ d-position o~ ~olld disp~r~lons o~ the acld-r~ist-
ant type on a water soluble lnert ~ore material ~sucros~) has
3~ been do~cribed by A. Ha~egawa 0t al. ~Chem. ~harm. Bull. 33
l~g 161~). Thi~ mcthod involV~B a r~lativ~ly cumbor~ome pro-
cedure Or spray-coating th~ solid dlspersion onto the water-
;~0599Z
-- 3 --
~olu~le ~uc~o~e ¢o~ or w~ich a opeclal zlp~a~atu~ i8 re-
qulred. Th~ thu- co~ed uuoros~ partlcl-~ ar~ ~3pherical and
~mooth I ~.nd ~h~y canno~ b~ cosRpr-~s~d into tablet~ wlthout an
~Xtrd ~tep o~ granulatlon. Be~ide6, thl-l m~thod i~ not t;uit-
~e ~or ~olid di~p~rs$on~ of ~h~ rale~ miting~ ~pH-inda-
pend~nt) typ~ ~nco th~l~o solid di~perslons~ will allow al-
~ead.y in th~ ~c~ d environn~ent o~ the ~tomach the occurrence
Or ~qUeouo diffuoion~ which will di~solvQ th~ ~ores, changing
th~ ~orm oS th~ pa~t~cle~ ~nd m~lclng th0 relæaff~ eharacte~
10 tlos unpr-dictal~le tnd uncontroll~
~ t h~ now k~een ~ouna ~hat ~tor-$naolu~1e carrler par-
tlclos do not ha~o th~ al;~o~o dl~advantaga~, and that ~ranu-
l~t~ ~o~ ~ultip~rt~cul~to oral cempo~it~ons wherein a blo-
logic~lly ~tl~ compound lc lncorporatod ln solid di~p-r~ion
wlth a~ ~id-ro~i-t~nt or r-lo~e-llmltlng compound can b~
pr-parRd ~or~ lclently ~nd effectively by mixing thi~
~olld dl~per~on with wa~er-ln-olubl~ a~rriar par~cles.
Wh-n wator-ln~olublo c~rrior partlcl-~ ar- u~d, th~y
o~n 91~ply bo mixo~ wlth th- dispor~ion bo~or~ lt ls ~olid-
ified, wi~hout any need to actlvely dQposit th0 ~ol~d on ~h~
carrior coro3. A~t-r the compl~t- mixturo has ~olldl~led, it
io f~rther pro~esned to a g~anulate according to granu~atlon
mothod~ ~nown in the art, such as o~cillating~ vln~ or ex-
tru~lon.
The proce~s accordlng to tho inv~ntlon 1~ v~ry ver~a-
til~ ~in~ lt i~ Appllaabl0 to both acid-re~i~tAnt And
releas~-llmiting p~ep~ration~. Tne proc-~s lo Aloo vory
e~icl~nt sinoe no sp-clal app~r~tua 1~ r~quir~d ~or tho
slmple ~t~p o~ mixlng th~ water-insolublo c~rrior p~rtlcl
wi~h th~ dl~p-r~lon, and 61nc- duo to the gr~nulea b~lng
irre0ular in shape ~nd porous t~ey c~n be lmmedlate~y com-
pro~ed into t~blota.
Z~059~3;2
Thu~, tho pre~ant inY~ntion pro~vid~ a m-~hod for pr~-
p~rlrlq ~ granul~t~ ~or a multip~rtiGulat~ oral compo~ition
ba~ed on the l;ono~pt o~ ~olid dl~per~ion, wh~r~by a b~ologlc-
~lly ~t~v~ sub-tanc. i~ dl~p-r~-d in an ao~d-r-~Lstant or
5 r~ s~-llmltlng ~ nce us~lng the m~lting, the 501~ent or
thc ~ltlng-301~vent ~e~tho~l~ ch~raaterised ln ~hat be~ors t~e
di~per~ion i~ ~olidlfi~d lt ~ ix~d w~ th w~lter~ solubl~
carr~-r part$cl~ wh-r-after th- co~pl~t~ ~nixtur~ 1~ furth~r
proo~e~l ~ccor~lng to granul~ on m~ known in th~ ~t.
n
The ~nv~ntion al~o provi~s yranulati~ for multl-
~rticulat- oral compoo~tlon~ comprl~n~ a bloleqlcally
act~v~ ~u~ na~ ~ n 301id d~ e~porsion with an ~¢~d -r~ tant
~nd~or ~ releaso~ iting compound, characterlzed ln th~t the
lS ool~d d~pero~on 1- mlx~ with w~ter-in-oluhl~ aarri-r p~r-
~icle~ ~
It wLll 2:~a ~pproalat-d th~t ~n prinoipl~- ~ny ~lolo~lc-
ally activo oompound ~an bo lncorpor~tad in th- granulatca
~or multlpartlculAte oral compo~i~iona of thls lnvention, and
ln pa~tlcular tho~e çompo~nd~, o.g. tho therap-utic tPoly~
peptl~-, whlch aro ~nCitivQ ts ~ld o~ to dlge~tive onzymes
and thos~ whioh Are diB~greeabl~ to th- stomach, h~t tha~ th~
maln applicatlon o~ thl~ lnvention lies with compound~ which
are meant to act looally ln th- int~tlne. ~xAmplo~ of th-
l~tter ar~ cortlco~torolds an~ non-~teroldal antl~lnrlamma-
tory compound~, espeGlally beGlom~tha~on- 17~21-dipropionate
an~ ~- or 4-amino-o~llcyllc acld or t~elr d~rivative~,
Furth~r example~ are blamuth compound~, spaclally Colloid~l
Bl~mu~h SubcltrAt~. It wlll b~ ~ppr~ciated th~ ~wo or moro
blologically A~ive compound~ can al~o be incorpor~ted ln
compo-itlon accordlng to th- lnvontlon.
Aaid-re~i~tan~ and relea6e-limiting compound~ to be
3S u~ed in the compo~itionu according to ths invuntion may be
any one or ~ comblnatlon o~ the compound- known ror thl6
purpo~o in th~ art. ~xamplo~ of known acid re~iatant com-
3~
.
- 5 -
pound~ ~r~ polymothacrylate-, e~p~oi~lly tho~o known under
th~ na~ of ~UD~AGIT-~ And -8, hy~roxypropyl m~thylcellulo
phth~ , cellulos- aoetat~ pht~alat-, c~llulo~ ac~tate
tri~ tat~, polyvinyl ~otatR phthalate, and ~h~llac.
S EUD~A~IT-8 h~s ~n ~ound to b~ a pr4~ra~1~ aal~ re~i~tant
~o~pound.
Exampleq o~ known rel-a~e-llmltin~ compounds ar~ th~
poly~h~crylat-~ k~own und-r th~ n~m~ EU~RA~ R~ and
-NE~ ethylc~llulo~a and polyvlnyl Aa~tatQ, ~tty acld~ ~u~h
a~ ~te~ric acid, ~Atty aaid R~t-r~ ~ush a~ PRECIRO~, long
~hain al~phatl~ ~loohol~ ~uah a~ c~tyl, ~t~aryl, ceto~taaryl
and myrl~kyl aleohol~ hyd~o~ennt-d ~gst~ble oil~ ~u~h a~
hydrogenated ca~or oll and hyd~og-n~t~d cottons~ed oll,
lg WAXo~ su~h ~n b~a- wax nd dl~tlll-d monoglycerid~ ch a-
glyaeryl mono~tGara~. EU~RAGTT-R8 has bRen ~ound to b~ a
pr~-rabl~ rel~se-limltln~ ~ompound.
Th- p-rc-ntag- o~ the biolo~l~ally aotiv~ compound
~w/w) in tho aolid di~per-lon oAn yAry bqtw-~n 0.01-99%, do-
pendin~ on tbo tho aomponent- u-~d. Whon th- blolog~cally
a~tlv~ ~ompound i~ ~ cor~lcost-ro~d ~uoh aG b~clomothaaone
17,21-dlprop~onat- it- poroontag- ~w/w) in tho olid di~p-r-
~lon is pr-~erably 0.1-40~, mor- pr~rably ~ %. Wh~n th~
blologlcally a~tlvo c~mpound 1~ a non-~terol~al antl-
lnrla~ma~ory oompound such a~ 5- or 4-amlno-salicyllc acl~
lts p~rcentago tw/w~ ln the solld dlsperslon is pre~erably
20-90~, more prererably ~o-80~.
For th~ dl~perslon o~ the biolo~la~lly aotive materla~
ln the aqid-renietant or relaaa--limiting ~ub~t~nc~, ~n
organic or An aqueou~ olv-nt mny be u-ed.
As an organic solvent, m~thylon~ chlorid- has b~n
3g ~ound to b~ u~orul to dlsper~e steroi~s, such a~ beolo-
methasone l7~ diproplonatQ~ ln rRl~a~o-llmltln~ ~ub~tances.
For the dlsperslon o~ s~ld s~orolds in acld re~is~an~ ~ub-
20() ~392
-- 6 --
6;tanG~, and o~ non-~t~roidal ant~ln1am~atory aompoundn
~u~h aJ S- e~r 4-ualno-sal ~ oyl lo aoid in both acid-r~ tant
arl~ ~el~a~-ll~lt~ng ~ompounds, a m~xture o~ a~out qual
wolg~t~ o~ othanol and ~thyl~no chlorlda ha~ b~-n ~ouncs to
5 b- v-ry u~ l a~ olvont.
Wl~qrl an a~u~ou~: solven~ mploy~d to ~ ?ersa ~
wn~Qr-oolu~l- biolog~eally aat~v~ sub~t~ , e.g. a ~hera-
peutla p~ptl~ tho a4id~0~1atant or relf~as--limiting
lO compoun~ aquoou~ polym~rl~ p-~-ionl~ have ~n roun~ to b~
par1:1cularly u~Q~ul au the a~ous ~olvent. ~!xample~ o~ the~e
ar~ agu-ou~ dl~pqlr~lon~ o~ polymet.haarylatn~ such as
EUDRAGI~r--L--~O-D, lC~JDl~AGIT-~L--30--D, ~5UDR~O~-RS--30--D and
EUD~%AeIT-Nl~-30,-~,0 or -50D, a~ueou~ dioporslonn o~ ~u3D~lcron
15 ~thyle!411ulo3~ ~pher-- ~AQUACOA~) and A~aueou~ di~per~lon~ or
oub~icron ~;ellulo~ tJltO phthAlate 4ph~res (ACUA~rERI~).
ExamplR~ o~ w~t-r-in~olubl~ ~arrl~r- to b~ uoad, ~lngly
or ln comb~na~on, in th- compo~itian~ aoc~rdln~ to the ln-
v-ntion are powd~r~d a~llulo6~, ~icroary~allina aellulo-~,
~tarah~ olloidAl ~ on dioxido~ ~-ntonite, magneo~um
alu~lnum ~llloate nn~ kaolln. Mloroory~allln- c411ulo~e,
suoh a~ i~ known und~r the propri~tary name AV~EL, ha~ been
round to bo a pre~rred carrior.
~ ha pr-$~rr-d m~an slza o~ the carrl-r particles 1~
about 0.1 mm, and the pre~rrod mean particlo ~lze Or the
granulato (carrler plu~ ~olld dispersion) is 0.1-2 mm, m~r~
pr~erably o.~-1.2 mm.
The granulates accordin~ ~o the invention can be incor-
por~tod in any o~ th~ pr-paratlon~ ror oral ~ppllcation known
in the art, ~uch as ~ach~ts, cApsul~s an~, pra~-rably,
~a~le~, op~ionally also contalnlng pharmaceutlcally aacept-
3~ ablo ~xo~piont~.
200~99
-- 7 --
Tableto contalning th~ granulat~ according to the
ln~entlon have the practioal advant~g~ wh~ ch ar~ ~nhor~nt to
ta~leto in genoral, and add~tlonally th~y have t~ ad~antage
o~ ~-ing multi-part~cul~te co~pooition~, in that th~y d~s-
lntegr~te ln the ~tomach, rel~ing th- gran~ , which ar~
~ma~l anou~h to 1~VQ the ~tomaoh rapldly And r~ bly.
Alternat~vely, t~bl~t~ ~ont~ining th~ grnn~lata~ a~ording to
tho invontlon can b~ lR~t to dl~lnt~r~t~ in a 6~all A~oUnt
o~ water, r~nd~rin~ a homogeneou~, drinkabl~ d~ ~per~ion.
It i~ known, o.g~ f~om ~.8. Davi~ et al., ~U~ 1986 2~
88~-892, thAt thR gastric emptylng o multl~articulate oral
~ompo~ltlon~ rea-mble~ ~hat o~ liquid do~Ag- ~or~ and
dl~er- ~rom that o~ th~ biq~er ~lngle unlto. While the
lntootinal tranoit tlm~ i~ approximatoly th~ eamo for th0
three do~age ~orm- ~n ~oth ~aAted and ~ed lndlviduAl~, the
ga~tr~c emptying o~ nlngl~ unlt~ whlah do not dl~integrato ln
tho ~tomaoh t~nde to b~ ~low and orratla, ~-p~ai~lly ~rom
~ull ~tomAah. Thero~oro ~hore 1~ an inhorent advant~g~ to
multiparticulat- do-ago ~or~, abovo ~lnql~-unlt tablets.
The inv~ntion th~fore al-o provld~ multlpartl~ulat~
eontroll~-rel-a~ oral composition~, in partiaulAr ta~lets,
aon~ainlng tho gr~nula~e~ Or the inv-ntion.
2~ ,
The rollowlng examples illu~trate the inventlon.
zoos99z
~L
100 g o~ th~ acitl-reslstant EU1:1RA6IT-8 w~ro ~l-nolvcd
ln a ~lxtur- Qf ~40 . 5 g ~n~thylene ohlori~e an~ ~40 . 5 g
5 ~thanol 96%. ~hon, lS g beal~n~ethasone 17, 2~-dipropi on~t~ ~A~
dls~olvQd in the ~bo~e ~lJD~UGI~-8 ~olutlon, and thiA ~olution
watl ~lo~ly (ln ~ ~n~lt~ s~-~ to 385 g ~f the wA~r~inool-
ubl~ c~rr~ er AVlClt~ P~ 102 ~n a plane~ m~xer, working~ At 60
r~volutlon~ per ~ nut~ . Th-~ compl~t- mix~uro wao p~rtially
10 d.rl~d dur~ng on~ hour at 50-C, to a ~olv~nt content of 10-
15%, ~nd u~quently pa~ed through an 03c~11atirlg s$-ve o~
1. 0 D apertur~ h~ r-~ul~lng gr~nulate ~as ~urth~r drl~d
durlng 12 ho11r~ at 50-~0 ~:, ~o c:onot~nt w~$s~ht . Th- batch o~
g~anul~, now r~dy ~or ~urth-r proc~ ing, h~d A tOt~ll
lS w~ ht o~ abol~t 500 gr~ 0 gra~DeS o~ lt had ~ ~r~ ~ols~e
of 1~0 ~ t~ ra~dual contont o~ thAnol an~l methylen~
chloridQ, dotarmin~ by ~C~ WaB 1.5% and 0.015%, re~p-ctive-
ly.
ao ~ho granul~8 hQd ~o following partlcl~ ize dlotr~buti~n~
LL~gn~15n~ Psrc-nk~a~ Of to~l
100~ ~m 0.~
1000-800 n 4.6
25B00-600 " . 19.4
600~400 " 33~7
400-200 ~ 29.4
~ 200 n ~2.0
Ther~al analycL~ p~ov-d the mat~rl~l o~ ~h~ svlld dlo-
per~ion to be d~ rent ~rom Q nimplo me~hA~lcnl mix of the
sam~ concentr~tlon~ o~ be~lomethAaone 17,21-dipropionate
cryst~l~ and ~UD~AGIT-S. Whll~ the mix d~mon~trated a oharp
endotherm ~t al~ C whloh i~ ~haracteristl~ o~ ~clom~tha~vn~
3~ 17,21-dipropionat-, the ~olld di~p~r~lon had no endotherm up
to 230'~.
X005''39~
The c:ontent o~ baclo~n~th~e~on~ 17, 2 ~-dipro~ion~ in the
g~anule~ wa~ 3 . 0% w~w, A~ dete~ d by HPLC,
Th~ d~ ratios~ ad~u~,ranl:~ Ks~ on-C:L ar~ l PH
102, both in the gu~ tl~e of 2~ g, w6~r~ add.od to 500 g of
th~ gr~nule~ of ~3:xampla 1 and ~ixed ~uring ~ lnute6. ~ub-
ntly 5. 5 g oP th~ lul~ aagne~lus~ ~t~aratQ was ~dded
10 ~n~ s~lxed ~urin~ a fur~h-~ a m~nut~o. ~he ma~s w~ ~chen fed
to ~n excenter pr~oo table'cting maohine, p~oduoin~ c:on~ave
ta~l~tc ha~.rlng a dl~mot~r o~ 7 m~n, A h~dne~ o~ 9-11 Rp and
~l~int~gratlng ~ ( lnto tho g~nu~ n 0 .1 N ~1 a'c
37 , o~ 3-5 mlnuta~ The tabl~t~ w~ighod 112 . 3 mg apiece,
15 contairlinS~ 3 ~g beolometha~on~ 21~rd~propionate and 20 mg
~UDRAGIT-S .
Th~ di~olution r~t~ of tha~ tablet~ wa~ t~t~d
~ccordin~ to UgP-XXI at 37', wlth the paddle ~tirred at 75
20 rpm. One tablet wao put in a medium o~ 4D0 ml 0.1 N HCl t 2%
cetomAorogol 1000 ~p~ 1. 3) . A~t~r 30 mlnut~s tha p~l W8
rai~d to 6. 5 or 7 . 0 by add~-nq 45 ~nd 50 ml ro~pectively o~
20% Ns3P04.12~20 and mak~n~ u~ to 500 ml with water, ~fte~
whioh tho pH w~o c~leaked and exaatly ~d~usted u61n~ a few
2S drops o~ 4N NaO~ or 6~ HCl. 13oelom~thA~on~ 17,21-dlpro5~lon~te
was do~ec:ted ln samplos or the rn~ium taXon at ci2rerant
time, whereby the HPLC m~tho~ wa~ used for ~uantification
aga~nst a 3tandar~ oS 6 ~g/ml b~clom-tha~onl- 17~zl-dlpropion-
atll in pho~phate bur~er o~ pl~ 7 . O ~ 2~; c~omacrogol lOOû . The
30 r~sult~, as whown in elgur~ l, olearly demonstrate a p~-
dopondant relea~
62.5 g o~ th- rel~a~-limitinq compound EUDRAGIT-RL
were dissolv~3d in 300 g methyl~n- chlorlde. Then 7 . 5 ~ b~clo-
metha~one 17~2l-dlpropionate was disfiolved in th~ above
~OOS992
EUDRAaIT-RL ~olution, and thio ~olutlon wa~ ~lo~ly (in 5 min-
utes) ad~d to 190 g o~ ~VICE~ PH 10~ n ~ plan-t mlxer,
worklng at 60 revolutlons p~r minut~. ~ho com~lotQ mlxtur~
wa~ p~rtlally dried durlng on~ hour at 50~. to ~ ool~nt
S a~nt~n~ of 10-15~, and ~b~gu~ntly pa~-ed through an o~
~tlng ~i~V4 of 1.O ~ aporturo~. ~h- reuultln~ granulAto wao
~urth~r drlod durlng 12 hour~ at ~0-60-~, to conAtant we~ght
Or about 250 g~ . 50 gra~a o~ it h~d a ~ree VolUm4 ~
198 ~1. It~ rooidual cont~n~ of ethanol and methylen~ ~hlor-
ide, dotRrm~n~d by GLC, was 0 . 012~.
~hQ granu~e~ h~d t~- followin~ partialo ~lse diutributlon;
~D~ ~,~entaae o~ total
~ 1000 ~111 2 ~ 6
1000-8~0 ll 21~ 3
~00-600 ~ 3 0 . 2
600--400 n 26 . 0
400-200 ~ 14 ~ ~
caoo ~ 5.0
~ h~r~al analycl~ prov~d the ~ateri~l o~ th- ~olid dl~-
por~ion to bD d~ r-nt ~rom a ~lmplo m~ch~nlcal m~x o~ ~he
~a~e conc-ntratlon- o~ b~olom~tha~ono 1~,21-dipropionat~
2~ cry~tal~ and EUDRAOIT-~8. While th~ mix d~mon~tratod a ~harp
~ndoth-r~ at 210'C whlah i~ ohar~otorlstlc o~ baclo~otha~one
17,21-dipropionate, th- olid di-p~r-ion had no ~ndoth-r~ up
to 230'~.
Th- aont~nt o~ h-~lom~tha-on-, 17,~1-dlproplonAt~ in
tho g~nule- wa~ 2.75% w~w, as detormln d by ~PLC.
E~p~g 4
Th~ di~int~gration ad~uvents Kollidon-~l and AVICEL
PH 102, both ln the ~uantit~os of 12~5 ~ w~re added to
222.5 g Or the granul~ o~ Example 3 and mixed during 10 min-
Z00599~
ut~ u~Q~ ntly 2 . 5 5 o~ the lubric:~nt magno~lum s'c0arate
Wll~ Added and ~g,xed durln~ ~ ~urth~r 2 minuteo. ~hs ma~ wa~
th~n ~ed to an exc~anter pr~:~o tablotting ;n~chin~, produ¢ing
~:on~ave tablet~ ha~lng ~ ~lameter o~ 7 mm, a hardn~ o~ 6-
5 7 kp snd a di~int~grating timQ ~ into th~ granul~~, in 0 .1 NHCI. a~ 37-C, o~ 3-5 min-~tQs. Th~ tablet~ we~hed 117 mg
apiec~ on~ainin~ 3 mg ~eclom-tha~one l7 ~ ~l-dipr~pionAte and
2 6 mg EUDRAGI~
lo Th~ olutlon rate of thn~ tabl~t~ wa~ ~e~od in
300 ~l pH 7 phosph~e b~ r I ~ tomacrogol 1000 in a
~-~X~r of ~00 ml . ~rh~ ~gnQt~ c ~tl~r~r had u rat~- of 600 rpm.
B~clometha~one l~ dlpr~plc~nat~ w~ det-at~d in ~a~pleo o~
th~ ~odlutn tA)c~n at dlff~r~nt time, wh-reby th~ HPLC ~ethod
~J w~- u-OEd ~or quantlficat~on, again~t a ~st~ndArd of 6 ,ug/ml
bec:lometha~on~ 17, ~l-dlp~p~nate in p~oophate bu~er of
p1~ 7 ~ O ~ 1% c~tomac~ogol 1000 . Th~ r--ults, a~ ~hown ln ~ig-
ur~ a, cl~arly domcm~trat~ st~in~d r~ aa~.
~ ~
75 Çl or th- rol-a-~-llmitin~ thyl~-llulo-~ R~d 75 ~ of
hydrog~nat~d ~A--t~r c~ll w-~- dl~ol~-d ~ n 1175 g Dlethyleno
chlorld~3. 'rhen 500 g S-~mlno-G;~ oyl~o a~id was di~p~r~od in
25 the a~o~ro solutlon, a~d thi~ dl-p-rnlon wa~l add~d in 2 ~nln-
ut~s to 450 g o~ thQ water-ln~oluble car~i~r powd~red cellu-
losn in a pl~ne~ mlxlar, worklng at 60 revolutlons pl~r mlnute.
Tho completH mlxture wa~ :~ub~ uently pa~ d through a s~lavo
o~ 1. 0 mm apertUro~. The r~ulting ~ranulate wa~ ~rl~d durlnq
30 1~ hour~ ~t ~O-dO~C, to aon~tant woight.
Th~ cll~olution rate o~ ~hese gr~nul~ wa~ 'cested
accordlng to U~P-XXS dt 37-C, with the paddle stlrring at
100 rpm. ~ mg granulQs we~e pu~ ln lOoo ml or pho~phate
3~ bur~er mqdlum or pH 7 . 5 to whlch was added O .1~6 PLURONIC: F6B .
At tim- intervals upto 12 hours the ab~or~a~c~ at 326 nm was
measured u~ing ~ ~p~ctrophotomcltQr equlped with a continuou~-
~00599;2
- la -
~low 2~a~pllng ~ystem. The 5-amino-~al~ cyllc aaid ~ontent wa~
c~loulat~d u0ing the ~b~orb~r.c:~ valu- of a ~3tandard o~
260 ,ug/ml of 5~ no-o~ ylic~ ~Gl~ in pho~phato buffRr o~
pH 7.S~ ~ontainlng O-lS ~2.,VROI~C F6~.
~h- 2~01~ult- , a~ ~hosm ln ~lgure 3, clearly demon~trat~
u~ta ~ ned r~l~a~ ~rom th~ g:rzmulo~ .
